EXPERIMENTAL CELL RESEARCH
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2025
·
IF 3.5
Zhen Yang,Feng Yan,Jiangwei Yuan,Manjun Yang,Jinyu Wang,Changqiao You,Kaiqun Ren
Background Cellular senescence refers to a condition where cells permanently cease division while maintaining metabolic activity. Doxorubicin (Dox) is known as an agent of induction of cellular senescence. This study aimed to explore the potential role of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exo) in mitigating Dox induced senescent. Method NIH3T3 cells were treated by various concentrations of Dox with or without hucMSC-Exo, cell morphology, viability, migration, senescence-associated SA-β-Gal staining were monitored. Cellular senescence was induced in C57BL/6J mice via administration of 5 mg/kg Doxorubicin, followed by treatment with hucMSC-Exo or metformin. Assessments included body weight, liver and kidney weight, colon length, SA-β-Gal staining of kidney and skin, molecular biomarkers of aging such as p16 INK4A , p53, and p21 Waf1/Clip1 to evaluate senescence status. Result We found that after the treatment of exosomes or metformin improved several aging-related phenotypes in both mouse and cellular models, including increases in body weight, liver and kidney weights, and the reduction of SA-β-Gal positive cells in kidney and skin tissues as well as cell models. At the molecular level, hucMSC-Exo resulted in the downregulation of inflammatory factors and senescence markers in liver and kidney tissues as well as cell models. Conclusion Our study demonstrates hucMSC-Exo may ameliorate Dox induced senescence either in NIH3T3 cells or in mice.
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ACS Biomaterials Science & Engineering
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2025
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IF 5.5
Jingchao Li,Yinghua Zeng,Fengjiao Liu,Xu Liao,Chongbin Zhong,Shujuan Dong,Yanbin Cai,Pingzhen Yang
Doxorubicin (DOX) chemotherapy is a cornerstone of cancer treatment, but its clinical application and effectiveness are severely restricted due to its life-threatening cardiotoxicity. Xanthohumol (XH), a compound from traditional Chinese medicine, is noted for its antioxidant properties and the potential to mitigate DOX-induced cardiotoxicity (DIC). However, its poor water solubility results in low biocompatibility, making it susceptible to immune system clearance, which severely restricts its application in vivo. In this study, we first identified and demonstrated that XH can effectively mitigate DIC by inhibiting ferroptosis. We designed a biomimetic nanodelivery system encapsulating XH within porous poly(lactic-co-glycolic acid) (PLGA) nanoparticles, further coated with an erythrocyte membrane (XH-NPs@RBCm). This system offers several advantages, including evasion of macrophage phagocytosis and prolonged circulation time, thereby enhancing the stability and bioavailability of XH in vivo. Treatment with XH-NPs@RBCm significantly reduced reactive oxygen species-dependent ferroptosis, improving the DOX-induced myocardial atrophy and cardiac dysfunction. Our study underscores the therapeutic promise of XH-NPs@RBCm in treating DIC through ferroptosis inhibition, offering key insights into biomimetic nanodelivery system development for DIC management.
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Brazilian Journal of Pharmaceutical Sciences
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2022
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IF 1.214
Meng Fansu,Ouyang Yong,Ma Qianqian,Du Manling,Liu Hui,Zhuang Yong,Pang Mujuan,Cai Tiange,Cai Yu
Doxorubicin (DOX) induced myocardial toxicity may limit its therapeutic use in clinic. Psoralen (PSO), a major active tricyclic furocoumarin extracted from Psoralea corylifolia, is widely used as an antineoplastic agent in treatment of leukemia and other cancers. This study is aim to find the protective effect of psoralen polymer lipid nanoparticles (PSO-PLN) on doxorubicin-induced myocardial toxicity in mice. The model of myocardial toxicity induced by DOX was established. The experiment was divided into 6 groups: normal saline group, DOX + Sulfotanshinone Sodium, DOX + PSO-PLN (3 mg/kg), DOX + PSO-PLN (6 mg/kg), DOX + PSO-PLN (9 mg/ kg), DOX group. DOX alone treated mice lead to a significant decrease in the body weight, heart weight, and increase in the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) markers of cardiotoxicity. However, DOX reduced glutathione (GSH) content and activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX), were recovered by PSO-PLN. And PSO-PLN also decreased markers of cardiotoxicity in the serum. Western blotting data showed that the protective effects of PSO-PLN might be mediated via regulation of protein kinase A (PKA) and p38. Our study suggest that PSO-PLN possesses antioxidant activities, inactivating PKA and p38 effect, which in turn protect the heart from the DOX-induced cardiotoxicity.
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ACS Applied Bio Materials
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2025
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IF 4.7
Yonghui Liu,Zongqian Ren,Yu Zhao,Dong Wan,Jie Pan
Conventional combination chemotherapy, which utilizes noncovalent bonding for self-assembly and encapsulation for drug loading and delivery, faces challenges in clinical application. The development of combination chemotherapy systems that enable multiple drugs to be contained within a single molecule to achieve synergistic therapy is an innovative concept for cancer treatment. In this study, a polymeric micelle named mPEG-GFLGAVPIAQDEVD-DOX&DOX was constructed through the covalent linkage of two chemotherapy drugs of doxorubicin (DOX) and the pro-apoptotic peptide SMAC (AVPIAQ) and then using the thin-film hydration method. The micelle can be specifically recognized by cathepsin B within cancer cells, leading to the cleavage of the peptide GFLG. This action facilitates the shedding of mPEG, thereby enhancing the efficiency of micelle uptake by cells. Upon internalization, the micelles release the encapsulated DOX, thereby promoting apoptosis and activating Caspase-3, which in turn cleaves the peptide DEVD. This process accelerates the release of DOX, thereby enhancing the efficacy of tumor cell killing. Subsequently, the pro-apoptotic peptide SMAC was exposed, which bonded to inhibitors of apoptosis proteins (IAPs) and inhibited their antiapoptotic activity, thereby accelerating tumor cell apoptosis. SMAC plays a key role in apoptosis by alleviating the inhibitory effect of IAPs on Caspase-3, allowing DOX and SMAC to act synergistically on tumor cells as cocktail therapy, achieving a double-killing effect, thereby improving therapeutic efficacy against tumors. These results indicated that the dual-drug polymer micelles prepared can significantly enhance antitumor therapeutic efficacy and reduce their side effects.
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Advanced Healthcare Materials
·
2013
·Vol. 2
·期 9
·1246-1251
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IF 0
Cuiling Du,Jie Zhao,Jinbo Fei,Yue Cui,Junbai Li
Doxorubicin, together with the modified polysaccharide (alginate dialdehyde), was used as a wall material to fabricate microcapsules through self-cross-linking by a template method. The microcapsules as-prepared are pH-responsive. Relevant scanning electronic microscopy, atom force microscopy and confocal laser scanning microscopy confirm the morphology of the uniform microcapsules. The spectroscopic results show that the microcapsules are assembled through electrostatic interaction and Schiff's base covalent bonding. Doxorubicin can be released sustainably from the capsules in buffer solution at a lower pH value. The cellular uptake of the microcapsules and drug release induced by acidic microenvironment are time-dependent processes. The cell cytotoxicity experiments in vitro demonstrate that the doxorubicin-based microcapsules have high efficiency to kill the cancer cells.
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DOI
Biomedical Materials
·
2026
·Vol. 21
·期 3
·035017
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IF 3.9
Lixia Fan,Xinren Xu,Huimin Luo,Yuke Xiang,Baixian Huang,Jun Wang,Ruixue Wang
Although chemotherapy remains a cornerstone of oncological treatment, its clinical application is severely hindered by the systemic toxicity and poor targeting efficiency inherent in conventional drug delivery systems. Given the relatively low levels of reactive oxygen species (ROS) in pathological tissues (<100 μM), there is an urgent need to develop stimuli-responsive carriers with superior sensitivity. In this study, we developed ditelluride-bridged carboxymethyl chitosan nanoparticles (DTeC NPs) as an innovative, ROS-triggered doxorubicin (DOX) release platform, using disulfide-crosslinked nanoparticles (DSC NPs) as a comparative control. Both nanocarriers exhibited a uniform particle size of approximately 200 nm and achieved high drug loading (∼25%) via electrostatic interactions with the polysaccharide backbone. Owing to the exceptional sensitivity of ditelluride bonds to oxidative environments, DTeC NPs demonstrated significantly accelerated degradation and drug release; notably, the cumulative DOX release reached 98.1% within 48 h in the presence of 100 μM H2O2. Furthermore, in vitro assays confirmed that DTeC/DOX NPs effectively enhanced cellular uptake. At a DOX concentration of 8 μg Ml−1, DTeC/DOX NPs reduced the viability of HepG2 and H22 cells to 27.4% and 33.9%, respectively, demonstrating significantly higher cytotoxicity compared to DSC/DOX NPs (35.9% for HepG2 and 45.8% for H22). In vivo studies further revealed that DTeC/DOX NPs achieved a tumor growth inhibition (TGI) rate of 72.29% in H22 tumor-bearing mice, markedly outperforming both free DOX (42.19%) and the disulfide-crosslinked control (60.81%). In summary, these findings underscore the immense potential of the ditelluride-crosslinking strategy for enhancing the precision and therapeutic efficacy of cancer chemotherapy.
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JOURNAL OF DRUG TARGETING
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2026
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IF 4.7
Ting-Ting Hu,Ying Ding,Yi-Ren Yao,Xin Zhang,Xi-Wen Zhang,Yang Gu
Doxorubicin (DOX), an anthracycline antibiotic, stands as one of the most potent and clinically ubiquitous chemotherapeutic agents for cancer treatment. Despite advances in clinical supportive care, strategies to prevent DOX-induced toxicity remain inadequate – with cardiotoxicity being a particularly devastating complication that can progress to heart failure. To address this unmet need, we engineered a novel core–shell biomimetic nanoparticle (NP) camouflaged with erythrocyte membranes, tailored for the targeted delivery of DOX to treat liver cancer while mitigating DOX-induced cardiotoxicity. This erythrocyte membrane-camouflaged biomimetic NP system exhibits an average diameter of 262.4 nm – an optimal size for prolonged systemic circulation – and possesses exceptional biocompatibility, coupled with enhanced responsiveness to the acidic tumour microenvironment. These synergistic features collectively augment the anti-tumour efficacy of DOX against hepatocellular carcinoma (HCC). Our findings highlight that the erythrocyte membrane-camouflaged NP serves as a promising biomimetic nanocarrier: it enables efficient delivery of chemotherapeutics to tumour sites while attenuating their off-target side effects (e.g. DOX-induced cardiotoxicity). This work thus provides a valuable strategy for improving the therapeutic index of anthracycline-based cancer treatments.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Jinsong Yin,Yuyun You,Juncong Mao,Jialong Qi,Xin Zhang,Yunfei Hong
Doxorubicin (DOX) is a widely used anthracycline whose dose-dependent cardiotoxicity limits its clinical efficacy. However, the mechanisms underlying its toxicity, particularly the regulatory network involving the Nod-like receptor protein 3 (NLRP3) inflammasome-gut-heart axis, remain incompletely understood. This study aimed to establish cellular and animal models of doxorubicin-induced cardiotoxicity (DIC) and investigate the role of the inflammasome in DIC-associated alterations in gut microbiota abundance. Rat cardiomyocytes (H9c2 cells) were treated with DOX 1, 10, 25, and 50 μmol/L concentrations to assess dose-dependent cardiotoxicity. In vivo, C57BL/6 J and NLRP3/MLKL/RIPK3 knockout (KO) mice received DOX (5 mg/kg, intravenous, every 2 days for 3 doses, cumulative 15 mg/kg) to establish a DIC model. We measured the physiological and biochemical parameters of mice peripheral blood using an automatic biochemical analyzer. Additionally, we quantified the mRNA expression levels of inflammatory factors using a reverse transcription polymerase chain reaction and observed cardiomyocyte apoptosis. Fecal samples were collected from each group for 16S recombinant DNA sequencing to analyze gut microbiota. DOX-induced H9c2 cell damage and inflammatory factor release activated the NLRP3 inflammasome and upregulated autophagy-associated proteins LC3I/II. NLRP3 KO attenuated DOX-induced cardiac damage, modulated the immune environment in mouse blood, and mitigated DIC. NLRP3 KO lowered the abundance of mucinophilic Akkermansia muciniphila and suppressed the cardiotoxic effects of DOX. The cardiotoxic effects of DOX were mediated via the NLRP3 inflammasome. NLRP3 inflammasome may mediate DIC by regulating the abundance of gut Akkermansia muciniphila .
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MOLECULES
·
2026
·Vol. 31
·期 6
·
IF 5.1
Lizhen Yu,Dandan Wang,Zhongtao Hu,Xuefeng Hou,Shuxue Wang,Wenzhi Zhang,Lihua Li
Monitoring the concentration of doxorubicin (DOX) was critical for tumor treatment, but existing methods failed to cross cell membrane. Here, an electrochemical platform for intracellular DOX detection in MCF-7 cells based on membrane-permeation strategy was developed. A modified gold electrode was prepared via electrodepositing AuNPs and assembling SH-DNA. Concurrently, the silica nanosphere/gold nanocluster-circular transmembrane peptide (SiO2/AuNCs-iRGD) composite nanoparticles with membrane permeability, tumor targeting, and imaging capability were synthesized. After co-incubation of SiO2/AuNCs-iRGD with MCF-7 cells and DOX, followed by co-incubation with the DNA-modified electrode, intracellular DOX intercalated into the DNA backbone, and redox-generated electrons were transferred to the electrode to produce a concentration-correlated electrochemical signal. The modification of the electrode, the morphology of the composite nanoparticles and the detection process were characterized by means of SEM, TEM, CV, EIS, DPV, fluorescence spectroscopy and laser confocal imaging. Under the optimized conditions, the proposed method exhibited a wide detection range of 0.05–300 μmol/L, with a detection limit of 0.01 μmol/L. Moreover, the modified electrode demonstrated satisfactory regenerability, and the proposed method showed excellent reproducibility and stability. The development platform could offer a new strategy for real-time assessment of drug concentration within cultured breast cancer cells in vitro.
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MOLECULES
·
2022
·Vol. 27
·期 24
·8858
·
IF 4.927
Gang Li,Ming Chu,Yingying Tong,Yuexin Liang,Shenghui Wang,Chengjun Ma,Zhenhua Wang,Wenna Zhou
Hippophae rhamnoidesL. is a deciduous shrub that contains many unique bioactive substances. This sea buckthorn possesses anticancer, antioxidant, anti-inflammatory, and cardiovascular protective properties. Herein, the effects of phenylpropyl compounds extracted fromH. rhamnoidesL. on doxorubicin (Dox)-induced cardiotoxicity were evaluated in zebrafish. Cardiac injury in zebrafish was induced using 35 μM Dox for 96 h, and 30 μM phenylpropanoid compounds were used as the protective treatment. The cardioprotective effects and mechanisms of the four phenylpropanoids were investigated using microscopy, behavioral analysis, acridine orange staining, western blotting, flow cytometry, and real-time quantitative polymerase chain reaction. The extracted phenylpropanoids could significantly relieve Dox-induced cardiac injury in zebrafish and inhibit cardiomyocyte apoptosis. The mechanisms of action were mainly related to the stability of mitochondrial biogenesis and function maintained by phenylpropanoids in zebrafish. To our knowledge, this is the first report on the protective effect of sea buckthorn against myocardial injury in zebrafish. Our findings provide support for the further research and development of sea buckthorn and its components.Keywords:sea buckthorn;zebrafish;doxorubicin;cardiotoxicity;mitochondria
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
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IF 6.51
Chan Jin,Jinbo Li,Xiaoguang Yang,Shuang Zhou,Chang Li,Jiang Yu,Zhaomeng Wang,Dun Wang,Zhonggui He,Yiguo Jiang,Yongjun Wang
Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8 + T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8 + T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.
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ANALYTICA CHIMICA ACTA
·
2022
·
IF 6.911
Shengzhong Rong,Lina Zou,Lingqiang Meng,Xiaoxia Yang,Jianmin Dai,Mengdie Wu,Ren Qiu,Yuting Tian,Xiaoyan Feng,Xiaowei Ren,Lulu Jia,Lan Jiang,Yongzheng Hang,Hongkun Ma,Hongzhi Pan
Cancer is one of the main diseases threatening human health in the world. Doxorubicin (DOX) is a common anti-cancer drug that can be used for chemotherapy to extend a cancer patient's life. It is our common wish that treatment process of cancer is efficient and secure. Therefore, it is of great significance to develop sensitive, rapid and accurate techniques for anti-cancer drug doxorubicin (DOX) detection. Herein, in our work, a ratiometric electrochemical sensor for DOX detection was designed, which based on MB@MWCNTs/UiO-66-NH 2 composites. The porous materials UiO-66-NH 2 magically shoulder double function in our ratiometric electrochemical strategy, which can reduce the interior error caused by the various complex materials. Specifically, on the one hand, it can be used to catalyze DOX, which can provide a great current signal to be detected, on the other hand, its special property of absorbing molecules was utilized to load materials as internal reference. Consequently, we chose methylene blue (MB) as the substance that can generate an internal reference signal, because it is a specific and stable electroactive substance. Then, we added MWCNTs as a part of the material modified on the ratiometric electrochemical platform to enhance the signal of the target due to its feature of good electrical conductivity . Under the optimized conditions, the ratiometric electrochemical sensor displayed a wide linear detection with the range from 0.1 μM to 75 μM and the limit of detection (LOD) of 0.051 μM. The applicability of this method in the analysis of actual human saliva samples has been confirmed by the results of selectivity , stability, and reproducibility tests, which was prospective in clinical application.
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